DE2051230A1 - Indolo square bracket on 1.2 square bracket on square bracket on 1.4 square bracket on benzodiazepine 6 ones and process for their preparation - Google Patents

Description

.-τ, ιιι, ρ

PATENT LAWYERS

DR. E. WIEGAND DIPL-ING. W. NIEMANN

DR. M. KÖHLER DIPL-ING. C. GERNHARDT 2051230

MÖNCHEN HAMBURG

phone: 55 54 7 «· 8000 monks 15, 19 October 197o

TELEGRAMS: KARPATENT NUSSBAUMSTRASSE 10

W 4o o87 / 7o 5 / Sch

AH. Robins Company, Incorporated Richmond, Virginia (V.St.A.)

Indolo- / i, 2-d // i, ^ / - benzodiazepin-ö-one and methods of making them

The invention relates to new heterocyclic compounds and in particular relates to indolo- / 1,2-d / ~ / Ϊ, ^ - benzodiazepin-o-ones, therapeutic preparations, which contain these active ingredients, and processes for the production of said compounds and preparations. the new compounds, which are described below, find application as physiologically active agents, in particular they are effective antidepressants and anticonvulsants.

The new indolo ~ / i, 2-d / - / i, 4 / ~ benzodiazepin-6-ones are represented by the following general formula:

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N (CHa) _n R

(D

in the

R is hydrogen, hydroxy, 1,2-dihydroxyethyl, lower alkyl lamino, di-lower alkylaraino, N-phenylcarbamoyloxy or Ν, Ν-diphenylcarbamoyloxy represents, v / obei phenyl is unsubstituted and non-substituted phenyl in which the mono-substituted phenyl is lower alkyl, lower Alkoxy, trifluoromethyl or a halogen with one Atomic weight is less than 8o,

R represents hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen with an atomic weight smaller as 8o,

η is a positive integer from 0 to 4 and its non- toxic acid addition salts.

A preferred group of compounds of the invention is represented by the following general formula II:

(II)

in the

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R has the meaning given above. While the connections of Formula II themselves have effectiveness, they are also available as intermediates for production new compounds of the invention in the field of formula I are advantageous.

The compounds of Formula I are pharmacological because of their pharmacological properties Beneficial effect on the central nervous system. The effectiveness becomes evident when the compounds can be used in the form of the free base or in the form of their non-toxic acid addition salts. The preferred one The form of the new compounds with a basic substituent in the 5-position is characterized as that non-toxic acid addition salt characterized by increased water solubility and convenience of administration.

The compounds of the invention have characteristic antidepressant activity; they are characterized by it to counteract the depressant effect caused by 2-oxo-3-isobutyl-9 »1o-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo- / c ^ ~ quinoline (tetrabenazine) in Hausen according to a modified method, in Englehardt, E.L. et al., J.Iled.Chem., Volume II (2), page 325 (1968), was induced. The ED ^ values were determined by the method of J.T. Litchfield and F. Wilcoxin, J. Pharm. other Exptl.Therap., No. 96, page 99 (1949). Among the new connections, the connections stand out in particular of Examples 1o and 11, 5- / 2- (W, li-dimethylanino) -ethyl / -indolo- / i , 2-d / - / i, ^ / - benzodiazepin-ö-one hydrochloride hemihydrate and 5- / 3- (IT, iT-Dinethylamino) -propyl / -indolo- / i , 2-d / - / i, ^ - benzodiazepin-o-one hydrochloride hemihydrate which have been shown to inhibit the effects of tetrabenazine. The compounds of the invention were intraperitoneally (i.p.) in Hausen in doses of un-

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administered about 20 to 100 mg / kg, and after about 30 min the mice were injected intravenously with 50 mg / kg tetrabenazine. The mice were observed for ptosis reversal and physiological behavior. The compound of Example 10 had an ED ₁ - value of 20 mg / kg, ip and the compound of Example 11 had an ED 1 - value of 9.6 mg / kg, ip

Certain of the novel compounds of the invention exhibit pharmacological activity of anticonvulsant ⁴ ") character. When they in cats using the Supra maximum Elektrοschock spasm technology Toman, JEP, among other things, J.Neurophysiol., No. 9, page 47 (1946) After conducting tests, the new compounds were effective in preventing convulsions induced by electric shock. This effect is best demonstrated at a dose of 25 to 200 mg / kg intraperitoneally, and preferably at a dose of 25 to 125 mg / kg. which were tested with regard to anticonvulsant effect, the compound of Example 2, 2-chloroindolo- / i, 2-d / - / i, 4 _ / - benzodiazepin-6-one is distinguished.

One object of the invention is therefore to develop new indolo / Ί , 2-d / - / i, 4 / -benzodiasepin-6-one to create the from Use as antidepressant and anticonvulsan $$ agents Bind Another object is to develop processes for the preparation of the new compounds, therapeutic preparations, containing these compounds and methods of using them. Other objects of the invention will be evident to a skilled person, and others Tasks will emerge from the description below.

) anticonvulsant

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In the definition of the symbols in the above formula I and where they continue to appear in this application, the terms have the following meanings:

As used herein, the term "lower alkyl" includes straight and branched chain radicals up to 8 carbon atoms and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, tertiary Butyl, amyl, isoamyl, hexyl, heptyl, octyl or others shown. "Lower alkoxy" has the formula -0-lower alkyl.

When halogen is mentioned, preference is, but not necessarily, a halogen having an atomic weight less than 80 used.

The term "carbamoyl" includes the N-phenylcarbamoyl radical just like the ΙΤ, Ν-diphenylcarbamoyl radical. The term "carbamoyloxy" has the formula -O-carbaraoyl.

The term "phenyl" includes the unsubstituted and monosubstituted phenyl radicals. Under the suitably substituted phenyl radicals there are phenyl radicals which are replaced by any radical which is not reactive or otherwise interferes with the reaction conditions, such as lower alkoxy, lower alkyl, trifluoromethyl or halogen. The lower alkyl or lower alkoxy substituents preferably have 1 to 4 carbon atoms arranged in a straight or branched chain can.

The compounds of formula I with a basic

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Substituents in the 5-position can be implemented and are mostly in a convenient form of the non-toxic pharmaceutically desirable acid addition salts used. Such salts also have improved water solubility. Although the non-toxic salts are preferred, any salt can be used as a chemical Intermediate product as well as in the production of another, but non-toxic acid addition salt The free basic compounds of formula I can easily be converted into their acid addition salts known procedures are implemented.

Suitable acid addition salts are those which derived from mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid and phosphoric acid} and from organic acids such as Maleic acid, oxalic acid, lactic acid, fumaric acid and tartaric acid. The preferred acid addition salt is the hydrochloride.

In general, the new compounds according to the invention are obtained from the known 2- (2-aminophenyl) indoles manufactured. A 2- (2-aminophenyl) indole is in a buffered solution of a weak acid, ζ "Bl, acetic acid, which is buffered with sodium acetate, dissolved and throw it with you a haloetyl halide, e.g. chloroacetyl chloride, converted to a (2- (2-haloacetamidophenyl) indole. A buffered Reaction medium is necessary for spontaneous .. ring formation from 2- (2-haloacetamidophenyl) indole to a 6-halomethylindolo- / i, 2-c / -ohinazoline. Sine maximum product yield is achieved when the acylation at 0 to 20 ° C, preferably at 5 to 10 ° ö, and in one Period of about 30 minutes to two hours elapses.

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After the acylation has ended, an excess of water is added to give the 2- (haloacetamidophenyl) indole precipitate, which is isolated by filtration and crystallization from a suitable solvent is cleaned.

The indolo - / !, 2-d / - / i, 4 / -benzodiazepine ~ 6- _: ones are produced by cyclizing 2- (2-haloacetaiaidophenyl) -indoles. The indole is in an inert organic solvent such as toluene. Benzene, dimethylformamide or dimethyl sulfoxide dissolved, with more polar solvents being preferred, and the solution is slowly added to a suspension of an alkali hydride such as sodium hydride in the chosen solvent. The reaction is preferably carried out at the reflux temperature of the solvent used for 3 to 5 hours. The indolo - / * 1,2-d / - / 1,4 / -benzodiazepin ~ 6-ones are made by adding an excess of Y / water to the cooled reaction mixture; and collecting the resulting precipitate. The crystalline products are further purified by crystallization from a suitable solvent.

The new compounds of formula I in which η is greater than O, i.e. η is a positive integer from 1 to 4, are made by reacting indolo- / 1,2-d / - / Ϊ, 4 / -benzodiazepin-6-ones with lower alkyl halides, CJ-hydroxyalky! halides, 1 ^ -dihydroxy-I-halopropanes, mono- and di-lower alkylamino-lower alkyl halides or other groups. The indolo - / ?, 2-d / - / i, 4 / · benzodiazepin-6-one is used in a dry inert solvent such as dimethylformamide or dimethyl sulfoxide dissolved, and the solution becomes an alkali hydride or an alkali arnide, for example sodium hydride or sodium

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amide suspended in the solvent used is added at or near room temperature. The reactants' with a replaceable halide are after cessation /

added to the evolution of gas, and the stirred reaction mixture is in general to a temperature of approx. about 50 ° C to 90 ° C for about 50 minutes to 26 hours>

heated. The raw products are obtained by extracting the re- ^v _; action mixture with a suitable organic solvent, such as benzene or chloroform, isolated. The products > are furthermore processed by acid-base extraction of the organic j

see solution purified, crystallization, column chromatography Treatment or conversion to an acid addition salt follows.

The 5- (o? -Hydroxyalkyl) -indolo- / i, 2-d / - / i, ^ / - benzodi- ■ ' azepin-6-ones prepared by the method as described herein are advantageous intermediate; products for the representation of additional compounds in the * area of the formula I. This is how these groups sit down with Phenyl isocyanates, phenyl and diphenylcarbamoyl chlorides to the corresponding 5- (CJ -phenyl-, cj-diphenylcarbamoyloxyalkyl) -indolo / * 1 , 2-d / - / i, 4 / -benzodiazepin-6-ones around. the Reactions are generally carried out in a dry, inert environment organic solvents such as benzene, - "chloroform, ( Tetrahydrofuran and the like at each reflux temperature de3 used solvent for the duration of approximately Performed for 2 to 20 hours. The i-roducts become common isolated from the reaction mixture by evaporation of the solvent and crystallized from a cleaned using a suitable solvent.

BATH ORIGINAL

1 0 9 8 1 8 /

Manufacture of the intermediate products

Working method 1 2- (2-aminophenyl) indole

A mixture of 150.0 g (0.67 moles) of phenylhydrazone, 2-aminoacetophenone and 500.0 g of polyphosphoric acid was made in a steam bath until the color changes from yellow to brown touched. The stirred mixture was cooled in ice water while an exothermic reaction occurred which raised the pot temperature increased to 125 ° G. After cooling, an excess of cold water was added to remove the excess To split polyphosphoric acid. The mixture was filtered, the solid residue dissolved in dilute sodium hydroxide and extracted with ether. The mixed ether extracts were dried and concentrated. The solid residue which was recrystallized from methanol, melted at 153 to 154 ° C and weighed 75 g (yield: 54 ^)

Analysis (C, JL ₂ ^)!

calculated: 13.45
found: 13.32

Working method 2 2- (2-Aj.nno-5-chlorophenyl) indole

A mixture of 2, o g (o, o39 moles) phenylhydrazone, 2-amino-5-chloroacetophenone and 50, o g polyphosphoric acid was stirred and heated to 125 to 130 ° C. At dia-

109818 / ?? PS

2Ü5123G

At this point an exothermic reaction raises the temperature to 150 ° C. The reaction mixture was stirred at a temperature between 140 and 150 ° C. for 10 minutes. An excess of v / ater was added to the cooled mixture. The solid that separated was collected by filtration and partitioned between dilute sodium hydroxide and ither. The ether layer was dried and concentrated. The indole, which weighed 7.9 g), was recrystallized from chloroform and

melted at 1o2 to 1o5 ° C.

analysis (C ₁₄ H ₁₁ ClN ₂ ): 69 C. 4th H 1 1 N 68 , 28 4th , 57 1 1 , 54 calculated: , 91 , 51 , 46 found:

Working method 3 2- (2-amino-5-bromophenyl) indole

A mixture of 6.5 g (0.021 mol) phenylhydrazone, 2-amino-5-bromoacetophenone and 20 g polyphosphoric acid was heated to about 100 ° C, where an exothermic reaction raised the temperature of the vessel to 130 ° C. The temperature was held at 130 ° C for 10 minutes and the mixture was cooled to about 90 ° C. An excess of water was added and the mixture was filtered. The collected solid residue was dissolved in ethanol and the solution was made basic. The basic insoluble product was extracted with chloroform and the combined extracts were dried and concentrated. The residue was recrystallized from ethanol and there were

ORIGINAL 109818/92 5 5

3.5 g (6ofi) of the product which ^{melted at 137 Ms Ho 0} C were obtained.

analysis (C ₁₄ H ₁₁ BrN ₂ ): 58 C. 3 H 9 N 58 , 55 3 , 86 9 , 76 calculated: , 73 .92 - , 59 found:

Using the procedures of Procedures 1 to 3, the following 2- (2-alino-5-substituted-phenyl) indoles were made manufactured:

2- (2 ~ Amino-5-methoxyphenyl) indole was made by reaction of phenylhydrazone made from 2-amino ~ 5-methoxyacetophenone and polyphosphoric acid;

2- (2 ~ Amino-5-trifluorinethyl'olienyl) -indole by reaction of the phenylhydrazone of 2-amino-5-trifluoromethylacetophenone and isolyphosphoric acid;

2- (2-Amino-5-Ä'thylphenyl) indole by reaction of the Phenylhydrazone of 2-araino-5-äthylaeetoj) henon and polyphosphoric acid;

2- (2-Amino-5-fluorophenyl) indole by reacting the phenylhydrazone of 2-amino-5-fluoroacetophenone and polyphosphoric acid;

2- (2-Anino-5-nethylphenyl) indole by reacting the Phenylhydrazone of 2-amino-5-methylacetophynone and polyphosphoric acid .

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Working method 4 /

2- (2-chloroacetamidophenyl) indole ;

To a stirred solution of 4.2 g (0.02 mol) 2- ■

(2-aminophenyl) indole in 15o ml of acetic acid was added a solution of 6.6 g _(f o o8 mole) of sodium acetate in 2ο ml of water. The mixture was cooled to 20 ° C. and 4.5 g (0.04 mol) of chloroacetyl chloride was slowly added. After the addition was complete, stirring was continued for 30 minutes and 150 ml v / water was added to the reaction flask. The crystalline precipitate was collected by filtration, dissolved in benzene and washed with water. The solvent was evaporated and the residue which crystallized on cooling was recrystallized from isopropyl ether. The white product weighed 2.5 g (yield: 43 ^) and melted at 10 8.5 to 11O ⁰ C.

Analysis (C ₁₆ H ₁₅ N ₂

C HN

calculated: 67.49 4.60 9.84

found: 67.67 4.66 9.7o

Working method 5

2- (2-chloroacetamido-5-chlorophenyl) indole

In a manner similar to that in procedure 4, 3.3 g (0.0136 mol) of 2- (2-amino-5-chlorohenyl) indole, the were dissolved in acetic acid, the 4.1 g (0.05 mol) of sodium acetate contained, with 3.0 g (0.027 IIol) of chloroacetyl chloride acylated. The temperature was below 10 ° C during the

BATH ORIGINAL

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Acylation held. The crude product was crystallized from isopropyl ether; it weighed 4.1 g (yield: 94 $) and melted at 155 to 158 ^° C.

analysis

C. H N calculated: 6o, 2o 3.79 8.78 found: 61.12 3.88 8.63

Working method 6 2- (2 ~ ghloracetamido-5- "bromophenyl) -indol

In a manner similar to that in procedure 4, 1o3 g (0.36 mol) of 2- (2-amino-5-bromophenyl) indole, which were dissolved in acetic acid containing 132 g (1.60 mol) of sodium acetate, acylated with 45.3 g (0.4o mol) of chloroacetyl chloride at a temperature below 10 ° C. The product was crystallized from ethanol isopropyl ether, weighed 114.5 g (yield: $ 87.5) and melted at 158 to 162 ^° C.

analysis (C ₁₆ H ₁₂ N ₂ OClBr): 52 C. 3 H 7th IT 53 , 85 3 , 33 7th , 7o calculated: , o9 , 37 , 59 found:

The following 2- (2-chloroacetariido-5-substituted-phenyl) -indoles were obtained by acylating the corresponding 2- (2-amino-5-substituted-phenyl) -indoles with chloroacetyl chloride in the presence of acetic acid, which was buffered with sodium acetate, in accordance with the procedure

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ren in the working methods 4 "to 6:

2- (2-chloroacetamido-5-methoxyphenyl) indole; 2 - ^ - chloroacetamido-iij-trifluoromethylphenyl) indole; 2- (2-Chlorace taraido-5-ethylpheny 1) indole; 2- (2-chloroacetamido-5-fluorophenyl) indole; 2- (2-chloroacetamido-5-methylphenyl) indole.

The invention is illustrated below with the aid of examples.

example 1 Indolo /! , 2-4 / - / Ί, 4 / -benzodiazepin-6-one

A solution of 6.0 g (0.02 Hol) 2- (2-chloroacetanidophenyl) indole in 50 ml of dimethylformamide was slowly added to a suspension of 0.51 g (0.021 mol) of sodium hydride in 150 ml of dimethylformamide. The mixture was refluxed for 5 hours. An excess of water was added to the cooled reaction mixture and the precipitate was collected by filtration and air dried. The crude crystalline product containing 4.5 g (G6fj) weighed was ketone from Kethylisobuty! Recrystallized and melted at 270 to 281 ⁰ C.

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Analysis (C ₁₆ H ₁₂ N ₂ ^O ) ¹

OHN

calculated: 77.4o 4.87 11.28 found: 77.14 5, oo 11.18

Example 2 '* 2-0hlorindolo- / i, 2-d / ~ / i ^. / - benzodiazepine-one

A solution of 3.0 g (0.094 Hol) 2- (5-chloro-2-chloroacetaHidophenyl) indole in 25 ml of dimethylformamide were slowly added to a mixture of o, 24 g (o, o1 mol) Sodium hydride in 1oo ral dimethylformamide was added. The mixture was refluxed for four hours. After cooling, an excess of v / water was added to the reaction mixture and the resulting precipitate A was collected by filtration and isolated from isopropyl ether recrystallized. The product weighed 1.4 g (yield: 50 pounds) and melted at 257 to 260 ° C. with decomposition.

analysis

C. H N calculated: 67.97 3.92 9 , 91 found: 68.47 3.94 9 , 73 Example 3 2-IJromindolo - / "i, 2- & J- £ \ , 4 / -benzodiazepin-6-one

A turbidity of 1o5 g (0.29 mol) 2- (5-Bro? N-2-chloro-

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acetaniidophenyl) indole in 100 ml of dimethylformamide slowly to a stirred suspension of 7 »2 g (o, 3o Mol) sodium hydride in 500 ml of dimethylformamide was added. The addition took nearly 3 hours; then the mixture was refluxed for 2 hours. 1 1 water was added to the cooled reaction mixture and a tan solid component separated. The raw one Product was collected by filtration and triturated in cold methanol-water solution. The integral part, which was air dried weighed 95 g (yield: $ 100). A 6 g sample was recrystallized from benzene and melted at 267 to 269 ° C.

analysis (C ₁₆ H ₁₁ BrN ₂ O): 0 3 H 8th, 56 58.73 3 , 39 8th, 47 calculated: 58.81 , 49 found:

Using the procedures of Examples 1-3, the following 2-substituted indolo - / * 1,2-d / - / ϊ 14./-benzodiazepin-6-one by cyclization of the corresponding 2- (5-substituted-2-chloroacetamidophenyl) indoles produced:

2-methoxyindolo- / ~ 1,2-d / - / i, 4 / -benzpdiazepin-6-one; 2-trifluoromethylindolo- / i, 2-d / - / "i, 4 / -benzodiazepin-6-one;

2-A'thylindolo- / 1,2-d / - / "i, 4 / -bensodiazepin-6-onej 2-fluoroindolo - / "i, 2-d / - / i, ^ / - benzodiazepin-G-one; 2-methylindolo / i, 2-d / - / i, / ly-

Example 4 5 ~ methylindolo- / i, 2-d _ / - / i, 4 / -benzodiagepin-6-one

A solution of 8.0 g (0.02 mol) of indolo- / i, 2-d / - / * 1,4 / -benzodiazepin-6-one added in 25 ml of dimethylformamide. Moderate evolution of hydrogen was obtained during the addition. After the evolution of gas ceased, a solution of 5.7 g (0.04 mol) of methyl iodide in 10 ml of dimethylformamide was added dropwise. The reaction mixture was stirred for one hour at room temperature and an excess of water / water was carefully added. The mixture was extracted with Bezol and the benzene extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was recrystallized from chloroform-isopropyl ether, and 3.0 g (34 / S) of the product which ^{melted at 129 to 131 0} O were obtained.

Analysis (G ₁ ^ H ₁ .N ₂ O):

CHN

calculated: 77.84 5.38 1o, 68 found: 77.87 5.47 1o, 7o

Example 5
2-bromo-5 ~ iaothylindolo- / i, 2-d / - / * 1,4 / -benzodiazepine ~

A solution of 15 g (o, o46 Hol) 2-bromoindolo- / ~ 1,2-

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d./-/i, 4 / -benzodiazepin-6-one in 60 ml of dry dimethylformamide were slowly added to a stirred suspension of 2.04 g (0.046 mol) of sodium hydride in 100 ml of dry dimethylformamide. After the addition was complete, the reaction mixture was heated ungeführ 60 ⁰ C for 15 min and cooled to room temperature. A solution of 7.3 g (0.05 mol) of methyl iodide in 15 ml of dimethylformamide was added dropwise and stirring was continued for one hour. The reaction mixture was carefully added to 500 ml of water and extracted with benzene. The benzene extracts were washed with water, dried over magnesium sulfate and concentrated. The crude oil was chromatographed on a magnesium silicate column and the product was leached using an elution gradient of acetone-benzene. The product was recrystallized from benzene-isooctane, melted at 95 to 98 ⁰ C and weighed 7. og (yield: 44.6 ^).

Analysis (C-j ^ H-j

C H ST

calculated: 59.84 3.84 3.21

found: 6o, 23 4, o9 7.95

Example 6

5- (2-hydroxyethyl) indolo- / i, 2-d _ / - / "1,47-benzodiasepin-6-one

A solution of 20 g (0.081 mol) of indolo- / i, 2-d / - / ~ ¹ j4 / -benzodiasepin- ~ 6-one in 3oo nl dimethylformamide was added dropwise to a stirred suspension of 2.14 g (o , 89 mol) sodium hydride in 2oo ml of anhydrous dimethyl

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formamide added. The mixture was stirred under a nitrogen blanket until hydrogen evolution ceased. A solution of 10.1 g (0.081 mol) of 2-bromoethanol in 25 ml of dimethylformamide was added dropwise to the reaction mixture, and the solution was ^{heated at 75 to 85 °} C. for 24 hours. V / water was added to the cooled reaction mixture and the aqueous mixture was extracted with benzene. The benzene extracts were dried and fortified. The remaining solid component was crystallized from isopropyl ether and gave 17.0 g (755 ») of the product. The product was recrystallized from benzene-isooctane and melted at 147 to 150 ° C.

Analysis (C ₁₈ H ₁₆ N ₂ O ₂ ):

9.59 9.58

C. 5 H calculated: 73.95 5 , 52 found: 73.85 , 51 Example 7

2 -Bromo-5- (2-hydroxyethyl) -indolo- /! , 2-d // * 1,4 / -benzodiazepin-6-one

Using the procedure from Example 6, 32.7 g (0.1 mole) of 2-bromoindolo / i, 2-d / - / i, 4 _ / - benzodiazepin-6-one were obtained in 3oo ml of dimethylformamide with 5.3 g (0.12 mol) of sodium hydride in 2oo ml of dry dimethylformamide implemented with a subsequent addition of 12.5 g (0.1 mol) of 2-bromoethanol in 25 ml of dimethylformamide. That Crude product was isolated and crystallized from isopropyl ether to give 26.7 g (72; ') of material dissolved in benzene was dissolved and placed in a magnesium silicate column chronatofjrai.h. Using an elution

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gradient of benzene-acetone, 6 g of the product obtained, which melted at 135 "to 138 ⁰ C.

analysis

C. H N .calculated: 58.24 4, o7 7.55 found: 58.52 4, o8 7.5o Example 8 5- (2- _i / TT- (3-chlorophenyl) -carbaraoyloxy7-ätliylJ-indolo- f \ , 2-d / - / i, 4 / -benzodiazepin-6-one

3 , 5 g (o, o23 KoI) 3-chlorophenyl isocyanate added. The mixture was stirred and enriched for 20 hours. The remaining oil was finely ground in ethylene chloride and a white crystalline component was separated. MR ⁺ examinations confirm that the solid constituent is di- (3-chlorophenyl) urea. The solid component was removed by filtration and the piltrate was concentrated. The oily residue was finely ground in ether and the solid component was collected by filtration. The white crystalline product, which weighed 3.5 g (38.2), was recrystallized from chloroform-ether and melted at 136 to 139 C.

analysis

C. II N calculated: 67.34 4.52 9.42 found: 67, o7 4.46 9 ₅ 3o

) kornmarnotiijchc Reaunaria

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^BATH

Example 9

5- (2,3-Dihydroypropyl) -ihdolo- / i, 2-α / - / ~ 1,4.7-benzodiazepin-6-one

Following the procedure of Example 6, 8.0 g (0.032 moles) of indolo- / 1,2-d / - / i, 4 / -Benzodiaze-

pin-6-on in 50 ml of dry dimethylformamide with 1.7 g (0.035 mol) of sodium hydride in 75 ml of dry dimethylformamide reacted with subsequent addition of 3.6 g (0.032 mol) 3-chloro-1,2-propanediol in 25 ml dry Dimethylformamide. The crude product was isolated from the reaction mixture and repeatedly from chloroform-isopropyl ether recrystallized; 1.5 g ($ 14.4) of the product were obtained, which melted at 198 to 204.degree.

Analysis (C ₁ QH ₁₀ IT ₂ O,):

G H N calculated: 7o, 79 5.63 8.69 found: 7o, 44 5.56 8.71 Example 1o

5- / 2- (lI, H-Dinethylamino) -äthyl7-indolo- / i, 2-d / - / Ί »4 _r / -benzodiazepin-6-one hydrochloride phenihydrate

A solution of 5, ο g (o, o2 Hol) Indolo - / "1, 2-d / - / Ί , 4 / -benzodiazepin-6-one in 25 ml of dimethylformamide slowly to a stirred suspension of 0.98 g (0.04%) of sodium hydride in 50 ml of dimethylformamide admitted. As soon as the gas winding subsided a Lcuun / ;; of 5, ο g (o, o21 Hol) 2-Dinethylariinorithylchlorid-hydrochloride in 25 nl of dinethylfornamide slowly

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admitted. The mixture was stirred at 70 to 75 ° C. for 4 hours. The cooled reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in benzene and subjected to acid-base extraction. The benzene extracts were dried and concentrated. The crude residue, which weighed 4.7 g ($ 74), was dissolved into the hydrochloride salt converted, and recrystallization from isopropanol gave a product which at 190 to 200 ° C melted.

Analysis (C ₄₀ H ₄₈ Cl ₂ N ₆ O ₃ ):

C. 1 H 35 1 N calculated: 65.84 6, 39 1 1.52 found: 65.93 6, 1.52 example 1

5- / 3- (N _t N-Diinethylamino) -propyl / -indolo- / i _t 2-d / - / Ί, 4 / ~ benzodiazepin-6-one hydrochloride hemihydrate

Following the procedure of Example 10, 15.0 g (0.06 hol) of indolo - / * 1,2-d / - / "1,4 / -benzodiazepin-6-one reacted in 5o ml of dimethylformamide with 1.45 g (0.06 mol) of liatrium hydride in 15o ml of dimethylformamide with subsequent addition of 7.4 g (0.06 KoI) 3 ~ (N, N-Dinethylamino) propyl chloride in 25 ml dimethylformamide. The crude 1 product was isolated from the reaction mixture and placed on a magnesium silicate column Use of a benzene-acetone eluent. The main fraction weighed 8 g ($ 40). His little sample was molecularly distilled for analysis.

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Analy se (C ₂₁ Η ,,, Ν, Ο)

C. H N calculated: 75.64 6.95 12.6ο found: 75.36 8.89 12.47

The hydrochloride salt hydrate that was produced was filtered under a dry nitrogen atmosphere and melted "at 165 Ms 170 ° C.

analysis

C. H N calculated: 66.56 6.65 11, o9 found: 66.17 6.35 11, o3 Example 12

2-bromo-5- / 2- (II, N-dimethylanino) -ethyl / -indolo- / Ί, 2-ά / - / Ί, 4 / -benzodiasepin-6-one hydrochloride hydrate

Following the procedure of Example 10, 1o, og (o, o3o5 Hol) 2-bromoindolo- / ~ 1,2-d / - / i, 4 / -benesodiazepin-6-one in 50 ml of dimethylformamide was obtained at 1.47 g (o, o61 Hol) NatriurJiydrid in loo ml Dime thy If oraamid reacted with the following. Addition of 4 _} 58 g (o, o3o5 Hol) 2- (Ii, H-Diiriethylamino) ethyl chloride hydrochloride in 50 ml of dimethylformamide. The product was isolated from the reaction mixture and 6.5 g of (59->) '-3 free 3ase was obtained. The hydrochloride salt was prepared and obtained as the I-monohydrate which melted at 145 ° C. At this point the bond softened and melted over a wide area.

109818/9? Π 5

2Ö5T23Ö

analysis

C. H N calculated: 53, o5 5.12 9.28 found: 53.34 4.76 9.19 Example 13

2-Bromo-5- / 3- (E "_> N-dimethylamino) -propyl7-indolo / ί, 2-d / - / 1,4 / -benzodiagepin-6-one hydrochloride hydrate

Following the procedure of Example 10, 2o, o g (o, o54 hol) 2-bromoindolo- / i, 2-d / - / i, 4 _ / - benzodiazepin-6-one in 100 ml of dry dimethylformamide reacted with 2.45 g (0.04%) of sodium hydride in 100 ml of dimethylformamide. The reaction mixture was heated to 70 ° C Heated for 2 hours; then there was 3- (N, N-diraethylamino) propyl chloride added in 25 ml of dimethylformamide. The crude product emerged from the reaction mixture isolated and a glass-like residue obtained, which weighed 11.7 g (53? '). The hydrochloride salt was prepared and isolated as ilonohydrate, which melted over the range of 145 to 150 ° C.

analysis

C. H N calculated: 54, o3 5.39 9, oo found: 54, o9 5, o2 8.81

Using the procedures of Examples 3 to 13 the following connections were made:

BAD ORIGINAL 109818/925 ^

2-chloro-5- / 3- (N, N-dimethylamino) -propyl / -indolo- / Ϊ , 2-d / - / i, 4 / -benzodiazepin-6-one by reaction of 2-chloroindolo- / i, 2-d / - / i, 4 / ~ benzodiazepin-6-one with sodium hydride and subsequent addition of 3- (H, N-Dinethylamino ) propyl chloride;

2-trifluoromethy1-5- / 2- (N, N-dimethylanino) -ethyl / -indolo- / i , 2-d / - / i, 4_ / ~ benzodiazepin-6-one by reaction of 2-trifluoroniethylindolo- / i, 2-d / - / i, 4 _ / - bensodiazepin-6-one with sodium hydride and subsequent addition of 2- (N, N-dimethylamino) ethyl chloride;

2 ~ ethyl-5-ethylindolo- / i, 2-d / - / i, 4 / -benzodiazepin-6-one by converting 2-Äthylindolo - / "i, 2-d / - / 1,4 / -benzodiazepin-6-one with sodium hydride and subsequent addition of ethyl bromide;

2-methoxy-5- / 4- (H-methylamino) -butyl / -indolo- / Ϊ , 2-d / - / i, 4 / -benzodiazepin-6-one by reaction of 2-methoxyindolo- / i , 2-d / - / i, 4 _ / - benzodiazepin-6-one r.iit sodium hydride and subsequent addition of 4- (H-methylamino) butyl chloride;

2-fluoro-5- (3-hydroxypropyl) -indolo- / i, 2-d / - / i, 4 / -benzodiazepin-6-one by converting 2-fluoroindolo- / ί , 2-d / - / i, 4 _ / - benzodiazepin-6-one:; i with sodium hydride and subsequent addition of 3-bromopropanol;

2-ITluoro-5- (3- / ii, lI-di- (4-nethoxy phenyl) -car bamoyloxy / -propyl) -indolo- / i, 2-d / - / i, 4 / -benzodiazepin-6-one by reaction of 2-? Luoro-5- (3-hydro: cypropyl) -indolo-2-d / - / i, 4 / -benzodiazepin-6-one with N, N-di- (4-mothoxy-

2-Brorn-5- {2- ^ i- (3-trifluoromethylphenyl) -carbanoyloxy / -ätriylj -indolo- /! , 2-d / - / i, 4 / -bensodi r: zepin-G-one by reaction of 2-bromo-5- (2-lyaroxyeth; / l) -indoio- / ^; ! _f 2-d7 ~ / Ί, 4 / -ücnzodiazepin-6-one with 3-trifl'io; ■ -.othylpher.yliso-

109818/92 5

2-chloro-5-methylindolo- / i, 2-d / - / i, 4 / -benzodiazepin-6-one by converting 2-chloroindolo- / i, 2-d / - / i, 4 / -benzodiazepin-6-one with sodium hydride and subsequent addition of methyl iodide; and

2-chloro-5-butylindolo- / 1,2-d / - / i, 4 / -benzodiazepin-6-one by converting 2-chloroindolo - / "1,2-d / - / i, 4 / -benzodiazepin-6-one with butyl bromide.

Formulation and administration

There can be useful compositions that contain at least one of the compounds according to the invention produced with a pharmaceutical! will. Thus, the compounds can be presented in a form suitable for oral or parenteral administration. For example, compositions for oral administration can be solid or liquid and can be in the form of Capsules, tablets, coated tablets and suspensions accept, such compositions being carriers or Ingredients commonly used in pharmaceutical technology include. Suitable tableting agents are e.g. lactose, potato and corn starch, tallow, gelatin and stearic acid or silicic acid, magnesium stearate and polyvinyl pyrrolidone.

For parenteral administration, the carrier or component can be sterile, parenterally acceptable Liquid, e.g., water or a parenterally acceptable oil such as peanut oil contained in ampoules.

109818/9255

The compositions can advantageously be used as dosage units formulated with each unit adapted to contain a set dose of active ingredient to delivery; Tablets, capsules, coated tablets and ampoules are examples of preferred forms and dosage units according to the invention. Even though small amounts of the active materials according to the invention are A effective when a mild therapy is under consideration comes, or in cases of administration to living beings, who have a relatively low body weight, the dosage units are usually 5 mg or above and preferably 25.5o or 100 mg or even more depending on the emergency and the particular desired result. 5 to 50 mg seems to be an optimum per unit dose while usually being wider Ranges between 1 to 500 mg per unit dose. It is only necessary that the active ingredient or Active ingredient constitutes an effective amount, i.e. that a suitable effective dosage is obtained which is consistent with with the dosage shape used. It is it will be seen that several unit dosage forms can be administered at about the same time.

The following are examples of compositions formed in accordance with the invention:

1. Capsules

Capsules of 5, 25 and 5o mg of V / :. drug per capsule v / earth produced. With the higher amounts of active ingredient the amount of lactose can be reduced.

Typical encapsulation mix mg per capsule

Active ingredient - '5, o lactose 296.7

Strength 129, ο

Magnesium stearate 4.3

a total of 435.ο mg

2. Tablets

A typical formulation for a tablet containing mg of active ingredient per tablet is given below given .. The formulation can be used for other strengths of active ingredient by adjusting the weight of dicalcium phosphate uses v / earth.

mg per tablet

1. Active ingredient 5, ο

2. Corn starch 13.6

3. Corn starch (paste) 3.4

4. Lactose 79.2

5. Dicalcium phosphate 68.2

6. Calcium stearate o, 9

total 17o.3 mg

Ingredients 1, 2, 4 and 5 are mixed uniformly. 3 is used every 1o? 5 key in V / ater. the Mixture is granulated with starch paste and the wet Hasse is passed through a sieve of about 2.4 nm clear mesh size (8-mesh sieve) driven. The wet granules v / is dried and passed through a sieve of about 1.4 nm

BATH ORIGINAL 1 0 9 8 1 8 /? ? $ c

classified in clear meshes (12-mesh sieve). The dried ones Grains are mixed with the calcium stearate and compressed.

Further tablet formulations preferably contain a higher dosage of the active ingredient and can be composed as follows:

5ο mg tablets

Ingredients mg per tablet

Active ingredient 5ο, ο

Lactose 90, o

HiIo strength 2o, o

Corn starch 38, ο

Calcium stearate 2, ο

a total of 200.00 mg

The active ingredient, lactose, starches and dicalcium phosphate, if present, are mixed uniformly. The mixture is then granulated using water as a granulating agent. The wet granules are passed through a sieve of about 2.4 mm sieve (8 mesh screen) and dried at about 6o to 71 ⁰ C (Ho to 1So ⁰ F) overnight. The dried grains are passed through a sieve of about 1.7 mm clear mesh size (lo-mesh sieve), mixed with the correct amount of calcium stearate, and the lubricated granules are then converted into tablets in a suitable tablet.

109818 / 925S ^E: '' ^D original

3. Injectable 2% sterile solutions

Active ingredient 2o mg / cc

Preservatives,

e.g. chlorobutanol ο, 5% by weight

Water to top up

The solution is prepared, clarified by filtration, filled into glass bottles or vials, and sealed and treated in an autoclave.

1098 18/7255 =

Claims (1)

Claims φ. Indolo- / i, 2-d / ~ / i, 4 / -benzodiazepin-6-ones of the general formula (D CN (CHa) _n RO in the R hydrogen, 1,2-dihydroxyethyl, hydroxy, lower alkylamino, di-lower alkylamino, Ϊί-phenylcarbamoyloxy or Ν, Ν-diphenylcarbamoyloxy, where phenyl is the phenyl radical and the monosubstituted phenyl radical in which the substituent is a lower alkyl, a lower alkoxy, Is trifluoromethyl or halogen with an atomic weight less than 8o, R hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or represents a halogen with an atomic weight less than 8o, η is a positive integer from 1 to 4, and its non-toxic acid addition salts. 2.5 ~ / 2 ~ (N, N-dimethylamino) -ethyl / -indolo- / i, 2-d / ~ / 1, ^ / - benzodiazepin-G-one. 5. 5- / 3- (N, iy-Dimethylaraino) - -; ro r.y! / - indo 1 ο- / ί, 2-d / - / I, 4 ./- benzodiazepin ~ 6-one. 4. 2-Bromo-5- / 5- (N, lI-dimethylamino) -ethyl / -indolo- / Ί , 2-d / - / * 1, ^ - / - benzodiazepin-ö-one. 5. 5-methylindolo- / " ¹ , 2-d _ / - / i ^ / - benzodiazepin-ö-one 6. 2-Bromo-5-methylindolo- / i, 2-dy ~ / 1,4 / -benzodiazepin-6-one. 7. Indolo- / i, 2-d / - / i, 4 / -benzodiazepin-6-one of the general formula (II) in the R is hydrogen, lower alley, lower alkoxy, trifluoromethyl or halogen with an atomic weight less than 8o. 8. 2-chloroindolo- / i, 2-d / - / i, ^ / - benzodiazepin-G-one. 9. Indolo- / l, 2-d // * 1, ^ - benzodiazepin-ö-one. 10. Process for the preparation of indolo- / i, 2-d / - / i _t 4y-benzodiazepin-6-ones of the general formula 109818/7255 CN (CH ₂ ) _n R O (D in the R is hydrogen, 1,2-dihydroxyethyl, hydroxy, lower alkyl lamino, di-lower alleylamino, N-phenylcarbamoyloxy or ΪΤ, Ν-diphenylcarbamoyloxy, where phenyl is the Phenyl radical and the inonosubstituted phenyl radical means where the substituent is lower alkyl, lower alkoxy, Is trifluoromethyl or halogen with an atomic weight less than 8o, R is hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen with one atomic density less than represents, and η is a positive integer from 1 to 4, characterized in that that one is an indolo - / "1, 2-d / - / i, 4 / -benzodiazepin-6-one the general formula (II) in the R has the meaning defined above, with an alkali hydride, followed by the addition of a compound of the general formula 109818/7255 R (CH ₂ ) _n X in which R and η have the meaning given above, and X is a halogen, to a 5-substituted-indolo- / ΐ , 2-d / - / "1, 4 / -ben2odiazepin-6-one converts, and when R is hydroxy, 5τ (-hydroxyalkyl) -indolo- / Ί , 2-d / - / i, 4 ./- benzodiazepin-6-one with phenyl isocyanates and carbamoyl chlorides. 11. Process for the preparation of indolo- ^, 2-d / - / - benzodiazepin-6-ones the general formula • (H) in the R is lower alkyl, lower alkoxy, trifluoromethyl or Represents halogen with an atomic weight of less than 8o, characterized in that a 2- (2-haloacetamidophe nyl) -indole of the general formula in the 1O9818 /? 25E R has the meaning defined above and X is a halogen, with an alkali hydride to an indolo- / i, 2-d / ~ / i, 4 / -benzodiazepin ~ 6-one converts. 12. Pharmaceutical preparation antidepressant effect, characterized in that it consists of a) one effective amount of about 1 to 500 mg of an indolo- / i, 2-d / - / i, 4 / -benzodiazepin ~ 6-one the general formula (D CN (CHa) _n RO in the R Hydrogen, 1,2-Dihydroxyiithyl, Hydroxy, Lower Alky! Amino, di-lower alkylamino, N-phenylcarbamoyloxy or Ν, Ν-diphenylcarbamoyloxy, where phenyl denotes the phenyl radical and the monocubstituted phenyl radical, in which the substituent is lower alkyl, lower alkoxy, trifluoroniethyl or halogen of one atomic weight is less than 8o, R V hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or represents halogen having an atomic weight less than 80, and η is a positive integer from 1 to 4 ·, and b) one pharmaceutically acceptable carrier. 13. Pharmaceutical preparation with anticonvulsant 109818/7255 Effect, characterized in that it a) from an effective amount of 1 to 500 mg of indolo- / 1,2-d / - / Ίi4 / -benzodiazepin-6-one the general formula in the R is hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halogen having an atomic weight less than 80, and b) a pharmaceutically acceptable carrier this exists. BATH ORIGINAL